RESUMO
HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/genética , Cadeias HLA-DRB1/genética , Lapatinib/efeitos adversos , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lapatinib/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/patologia , Estadiamento de Neoplasias , Fatores de Risco , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.
Assuntos
Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Cadeias HLA-DRB1/genética , Quinazolinas/efeitos adversos , Alanina Transaminase/metabolismo , Alelos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Receptores ErbB/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/genética , Mutação INDEL , Lapatinib , Polimorfismo de Nucleotídeo Único , RiscoAssuntos
Proteínas Reguladoras de Apoptose/genética , Deleção de Genes , Indóis/uso terapêutico , Proteínas de Membrana/genética , Neoplasias/genética , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas/genética , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Quinazolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Proteína 11 Semelhante a Bcl-2 , Humanos , Indazóis , Lapatinib , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Prognóstico , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , SunitinibeRESUMO
Lapatinib is a clinically important component of the treatment for HER2-positive metastatic breast cancer and has an acceptable safety profile. Lapatinib-associated Hy's Law cases have been characterized using human leukocyte antigen (HLA) DQA1*02:01/DRB1*07:01 and Gilbert's syndrome UGT1A1*28/*28 genotypes. The HLA-positive cases had higher alanine aminotransferase (ALT) elevation, whereas the HLA-negative cases had a higher incidence of Gilbert's syndrome. The findings of our study, which extend this HLA association to lapatinib-associated serious liver injury, emphasize the importance of Gilbert's syndrome in the interpretation of Hy's Law and may lead to methods for enhancing patient safety.